This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The goals of this project are: 1) to investigate the survival and function of porcine islet xenographs in rhesus macaques using a novel Costimulation blockade-based regimen and 2) to prolong islet xenograph survival by optimizing new and existing stimulation blockade-based immunosuppressive therapies and testing new methods and sites of islet implantation. Using pancreatectomized macaque recipients, neonatal islets, and a Costimulation-blockade based regimen target the CD40L pathway, we have had excellent initial success with porcine islet transplantation;achieving long-term graft survival, function, and insulin independence. The clinical usefulness of anti-CD40L reagents was limited by significant incidence of thromboembolic complications. Building on these results we are looking at alternative immunosuppressive regiments targeting other Costimulation pathways such as CD40 and CD28. We have had encouraging but inconsistent results with these regimens. Some cases provided excellent xenograft survival. Current and future directions will focus on more clinically applicable reagents such as Tacrolimus and LFA-31g. Islets from pigs bred to lack the surface carbohydrate Gal on all tissues (Gal-KO) may circumvent the robust innate immune response that is usually mounted against transplanted xenogeneic tissues. Initial results investigating the transplantation of Gal-KO islets under cover of Costimulation blockade-based regimens have been extremely good and are ongoing. Each experiment employs significant Yerkes resources, including veterinary staff, Rhesus macaques, operating room time and staff, and pathology services.